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Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms

Nature Nanotechnology (2024)Cite this article

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Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.

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Fig. 1: PS regulates the dynamic assembly and liquid-to-solid phase transition of nuclear TDP-43 condensates.
Fig. 2: PS accelerates solid-like nuclear TDP-43 condensates formation by oxidizing chaperone Hsp70.
Fig. 3: TDP-43 cytoplasmic translocation and the formation of PS@TDP-43 complexes.
Fig. 4: PS@TDP-43 complexes promote cytoplasmic TDP-43 condensation and solidification.
Fig. 5: Molecular docking analysis of the effect of PS adsorption on the binding affinity of two TDP-43 molecules.
Fig. 6: PS intranasal exposure causes ALS-like neurodegeneration and liquid-droplet-like TDP-43 formation in mice.

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Data availability

The source data underlying the main text figures (Figs. 1–4 and 6 and Extended Data Figs. 1–4) and the supplementary figures (Supplementary Figs. 1, 4, 6, 7, 8, 10, 11, 14, 15) and videos (Supplementary Videos 1–8) are provided as source data files or deposited in Gene Expression Omnibus (RNA-seq) under accession number GSE264018. The description data for the TDP-43 structure were acquired from the AlphaFold Protein Structure Database (AlphaFoldDB) under the accession code AF-Q13148-F1. TDP-43 protein disorder region scores from Predictor of Natural Disorder Regions (PONDR; an online tool, http://www.pondr.com/).

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Acknowledgements

This work is supported by the National Key R&D Program of China (2023YFC3708303 to Y.S.), Strategic Priority Research Program of the Chinese Academy of Sciences (XDB0750300 to Y.S.) and National Natural Science Foundation of China (22176206 to Y.S. and 22174116 to E.S.).

Author information

Authors and Affiliations

  1. State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing, China

    Hang Sun, Bingwei Yang, Yang Song & Guibin Jiang

  2. Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, College of Pharmaceutical Sciences, Southwest University, Chongqing, China

    Hang Sun, Bingwei Yang, Qiong Li, Xiaokang Zhu, Erqun Song & Yang Song

  3. Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Cong Liu

  4. State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    Cong Liu

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Contributions

H.S. and Y.S. conceived the study. H.S., B.Y., Q.L. and X.Z. performed assays and contributed to data interpretation. E.S. and Y.S. supervised the experiments. H.S., C.L. and Y.S. wrote the paper. E.S., Y.S. and G.J. provided reagents and oversaw the research. All authors had input on the content of the paper and approved the final version of the paper.

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Correspondence to Yang Song.

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Extended data

Extended Data Fig. 1 PS exposure induces transgenic/endogenous nuclear TDP-43 granules formation in HeLa cells.

a, Representative images and the fluorescence intensity profile along the indicated white line of HeLa cells forming EGFPTDP-43 granules at 6 h after the indicated concentrations of PS treatment. b, The percentage of cells forming EGFPTDP-43 granules in (a). Data are expressed as means ± SD. n = 3, 50 cells per experiment, as determined by one-way ANOVA with Tukey’s multiple comparison tests (p = 0.0167 and 0.0012 for PS of 50 and 100 µg/mL vs. 0 µg/mL, respectively; ns, p > 0.05). c, Representative images and d, fluorescence intensity profile along the indicated white line of HeLa cells forming endogenous TDP-43 granules (arrows) in response to indicated PS exposure concentrations after 6 h. n = 3 independent experiments per group.

Source data

Extended Data Fig. 2 PS exposure-induced cellular stress and compromised organelles in HeLa cells.

a, Representative images of NAC inhibit PS-triggered nuclear EGFPTDP-43 condensates formation. NAC, 2 mM, PS, 100 µg/mL, 6 h. b, The relative ROS levels (using the DCF-DA probe) were detected by flow cytometry. Data are expressed as means ± SD, n = 3, as determined by one-way ANOVA with Tukey’s multiple comparison tests (Ctrl vs. NAC, p = 0.9742; Ctrl vs. PS, p < 0.0001; Ctrl vs. PS + NAC, p = 0.1539; PS vs. PS + NAC, p < 0.0001). c, Quantification of nuclear EGFPTDP-43 condensates number per cell in (b) (n = 10 cells). Data are displayed as the median +/− the interquartile range, n = 3, as determined by one-way ANOVA with Tukey’s multiple comparison tests (p < 0.0001; ns, p > 0.05; Ctrl vs. PS+NAC, p = 0.0081). d, Representative images of p-eIF2α expression levels in HeLa cells. GAPDH was used as internal control. e, Quantification of p-eIF2α expression in (d). Data are expressed as means ± SD, n = 3, as determined by one-way ANOVA with Tukey’s multiple comparison tests. (Ctrl vs. PS 6 h, p = 0.0404; Ctrl vs. PS 12 h, p = 0.0092; Ctrl vs. PS 24 h, p = 0.0300; ns, p > 0.05). f, Representative images of JC-1, AO and Magic red staining in HeLa cells after PS exposure. Red JC-1 aggregates indicate high MMP, and the green JC-1 monomers indicate low MMP; Lysosomal membrane permeability was detected by AO. AO in the intact lysosomes (red), cytoplasm (green); Cathepsin B release was detected by Magic Red staining. Magic Red (red), DAPI (blue). n = 3. g, Flow cytometry was used to quantify PS-induced MMP loss (JC-1), cell membrane damage (PI), lysosomal membrane permeability (AO) and Cathepsin B release (Magic Red). Data are expressed as means ± SD, n = 3, as determined by one-way ANOVA with Tukey’s multiple comparison tests (For JC-1 test, Ctrl vs. 6, 12, 24 h, p = 0.0075, p = 0.0002, p < 0.0001, respectively; For PI test, Ctrl vs. 6, 12, 24 h, p = 0.0371, p < 0.0001, p < 0.0001, respectively; For AO test, Ctrl vs. 6, 12, 24 h, p = 0.2378, p < 0.0001, p < 0.0001, respectively; For Cathepsin B test, Ctrl vs. 6, 12, 24 h, p = 0.0003, p < 0.0001, p < 0.0001, respectively).

Source data

Extended Data Fig. 3 Solid-like nuclear TDP-43 condensates formation is required for PS exposure-induced TDP-43 pathology.

a, EGFPTDP-43 transfected HeLa cells exposed to PS (100 µg/mL) followed by immunostaining with anti-pTDP-43 (Ser409/410). Nuclei are marked by dashed circles. b, The percentage of cells expressing pTDP-43 in (a). Data are expressed as means ± SD (n = 3, 25 cells per experiment), as determined by one-way ANOVA with Tukey’s multiple comparison tests (Ctrl vs. PS 12 h, p = 0.0121; Ctrl vs. PS 24 h, p = 0.0010; PS 6 h vs. PS 12 h, p = 0.0314; PS 6 h vs. PS 24 h, p = 0.0021; ns, p > 0.05). c, Representative images of phosphorylation levels of nuclear TDP-43 (N-pTDP-43). Lamin B was used as an internal control. d, Quantification of nuclear TDP-43 phosphorylation. Data are expressed as means ± SD (n = 3), as determined by one-sided one-way ANOVA with Tukey’s multiple comparison tests (Ctrl vs. PS 6 h, p = 0.8011; Ctrl vs. PS 12 h, p = 0.0018; Ctrl vs. PS 24 h, p < 0.0001; PS 6 h vs. PS 12 h, p = 0.0051; PS 6 h vs. PS 24 h, p < 0.0001; PS 12 h vs. PS 24 h, p < 0.0001). e, AmyT staining. Nuclei are marked by dashed circles. f, The percentage of cells showing AmyT in (e). Data are expressed as means ± SD (n = 3, 25 cells per experiment), as determined by one-sided one-way ANOVA with Tukey’s multiple comparison tests (Ctrl vs. PS 24 h, p = 0.0024; PS 6 h vs. PS 24 h, p = 0.0040; PS 12 h vs. PS 24 h, p = 0.0117; ns, p > 0.05). g, Representative images of HeLa cells expressing WT or A326P TDP-43-HA in the presence of PS (100 µg/mL). h, CCK8 assay showed the effect of PS-triggered TDP-43 LLPS on the viability of HeLa cells. Data are expressed as means ± SD (n = 3), as determined by two-way ANOVA with Bonferroni’s multiple comparison tests (PS 6 h, WT vs. A326P, p = 0.0153; PS 12 h, WT vs. A326P, p = 0.0069; PS 24 h, WT vs. A326P, p = 0.0465; ns, p > 0.05).

Source data

Extended Data Fig. 4 PS exposure triggers TDP-43 cytoplasmic translocation.

a, Three-dimensional reconstruction images of TDP-43 recruitment to SGs in Fig. 3a. b, Representative images of TDP-43 expression levels in the nucleus (N-TDP-43) and the cytoplasm (Cyto-TDP-43) in HeLa cells. Lamin B and GAPDH were used as internal controls for the nucleus and cytoplasm, respectively. c, Quantification of TDP-43 expression in the nucleus. Data are expressed as means ± SD, n = 3, as determined by one-way ANOVA with Tukey’s multiple comparison tests (Ctrl vs. PS 12 h, p = 0.0444; Ctrl vs. PS 24 h, p = 0.0464; ns, p > 0.05). d, Quantification of TDP-43 expression in the cytoplasm. Data are expressed as means ± SD, n = 3, as determined by one-way ANOVA with Tukey’s multiple comparison tests (Ctrl vs. PS 12 h, p = 0.0189; Ctrl vs. PS 24 h, p = 0.0240; ns, p > 0.05).

Source data

Extended Data Fig. 5 PS exacerbates the pathological tendency of TDP-43.

Schematic illustration of the role of PS exposure in the aberrant phase separation and pathology of TDP-43.

Supplementary information

Supplementary Information

Supplementary Figs. 1–16 and Tables 1 and 2.

Reporting Summary

Supplementary Video 1

TDP-43 condensates morphology, related to Supplementary Fig. 3.

Supplementary Video 2

TDP-43 condensates morphology, related to Supplementary Fig. 3.

Supplementary Video 3

TDP-43 condensates fusion event, related to Fig. 1b.

Supplementary Video 4

TDP-43 condensates FRAP analysis, related to Fig. 1c.

Supplementary Video 5

TDP-43 recruitment to SGs, related to Fig. 3a. TIAR, SGs marker (red), EGFPTDP-43 (green), DAPI (blue).

Supplementary Video 6

TDP-43 recruitment to SGs, related to Fig. 3a. TIAR, SGs marker (red), EGFPTDP-43 (green), DAPI (blue).

Supplementary Video 7

TDP-43 recruitment to SGs, related to Fig. 3a. TIAR, SGs marker (red), EGFPTDP-43 (green), DAPI (blue).

Supplementary Video 8

Partial RFPS and cytoplasmic TDP-43 condensates co-localize in the cytoplasm, related to Fig. 3f. EGFPTDP-43 (green), RFPS (red).

Supplementary Data 1

Statistical source data and unprocessed gels for supplementary figures.

Source data

Source Data Fig. 1

Statistical source data for Fig. 1.

Source Data Fig. 2

Statistical source data and unprocessed gels for Fig. 2.

Source Data Fig. 3

Statistical source data for Fig. 3.

Source Data Fig. 4

Statistical source data for Fig. 4.

Source Data Fig. 6

Statistical source data for Fig. 6.

Source Data Extended Data Fig. 1

Statistical source data for Extended Data Fig. 1.

Source Data Extended Data Fig. 2

Statistical source data and unprocessed gels for Extended Data Fig. 2.

Source Data Extended Data Fig. 3

Statistical source data and unprocessed gels for Extended Data Fig. 3.

Source Data Extended Data Fig. 4

Statistical source data and unprocessed gels for Extended Data Fig. 4.

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Sun, H., Yang, B., Li, Q. et al. Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms. Nat. Nanotechnol. (2024). https://doi.org/10.1038/s41565-024-01683-5

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